Glomerular kidney diseases are on the rise with no definitive treatment for proteinuric renal disorders available yet. Over the past years, we have shown that podocyte foot process (FP) effacement, proteinuria and kidney disease progression can be specifically induced by the action of a novel cytosolic cathepsin L variant (cCatL). cCatL hereby acts as regulatory protease that is induced during glomerular injury cleaving th GTPase dynamin, synaptopodin as well as CD2AP. These cleavage events have led to a novel concept that characterizes FP effacement as podocyte enzymatic disease. In this competitive renewal, we seek to clarify innovative ways to neutralize cCatL in an effort to treat glomerular disease more effectively. We will test the hypothesis that inhibition of cCatL activity in podocytes will improve glomerular disease. To test this hypothesis, we will perform a combination of in silico and cell culture studies and make use of our novel mouse model that is inducible for specific podocyte-expression of cCatL. Upon induction of podocyte cCatL, this mouse develops podocyte FP effacement and proteinuria. We will utilize this mouse and study inhibition of cCatL by a group of enzymes called serpins. Our initial focus will be on SERPINB13 (hurpin) which is classically located in the cytosol of skin cels and known to be a specific inhibitor for cathepsin L. We found inducible expression in podocytes and have created podocyte-specific knockout animals for SERPINB13 and also possess SERPINB13 transgenic mice to study how these enzymes will perform in the face of high cCatL. We will also analyze the effects of podocyte alkalinization on cCatL activity as normal podocyte intracellular pH is close to 7.3 but in disease is closer to the pH optimum for cCatL activity at p 7.0. We have preliminary data showing that alkalinized podocytes using for example L-glutamine supplementation are protected from proteinuria in the LPS mouse model. In sum, biochemical, cell culture and genetic animal models will be utilized in a novel multifaceted approach to tackle proteinuric renal diseases.